This invention relates to a process for producing optically active xcex2-amino alcohols. More particularly, it relates to a process for producing optically active xcex2-amino alcohols which are of value as drugs or their intermediates.
Ephedrines have been used for purposes of perspiration, antipyresis and cough soothing from the olden times, and particularly, d-pseudoephedrine is known to possess anti-inflammatory action. Pharmacological action such as vasoconstriction, blood pressure elevation, or perspiration is known for 1-ephedrine and it is used in therapy as a sympathomimetic agent. 1-Ephedrine is also used in the treatment of bronchial asthma. Specifically, processes for the production of optically active xcex2-amino alcohols, including optically active ephedrines, are useful in the manufacture of drugs and their intermediates; thus, there is a need for efficient production processes.
In the conventional process for producing a xcex2-amino alcohol with the desired optical activity, there was used a process by which a racemic xcex2-amino alcohol is obtained and then a specific optically active form is produced by optical resolution or asymmetric synthesis among others.
However, since the racemic xcex2-amino alcohol has two asymmetric carbons within its molecule, complicated steps had to be followed to obtain the specific optically active form. For example, according to Ger. (East) 13683 (Aug. 27, 1957), optically active phenylacetylcarbinol was produced from benzaldehyde by fermentation utilizing yeast and erythro-1-2-methylamino-1-phenyl-1-propanol (i.e., 1-ephedrine) could be produced by reductively condensing methylamine to the optically active phenylacetylcarbinol.
To obtain pseudoephedrine, the production is possible as described in U.S. Pat. No. 4,237,304: an oxazoline is formed from 1-ephedrine produced by the method described in Ger. (East) 13683 (Aug. 27, 1957), using acetic anhydride, and then the oxazoline is hydrolyzed through inversion to the threo form (i.e., d-pseudoephedrine).
As stated above, to produce pseudoephedrine with the desired optical activity from 2-methylamino-1-phenyl-1-propanone, steps are necessary such that ephedrine in the optical active erythro form is once produced and then it is inverted to the threo form. Hence, there arise problems that the number of steps grows and leads to complication and that the yields lower.
Furthermore, in the production of the pseudoephedrine while a substantial amount of diastereomers is produced as byproducts during the reduction of the starting ketone, the recovery of the diastereomers for their use as raw material is difficult, which is economically disadvantageous.
In addition, according to the method as described in the publication of JP, 8-98697, A, it is possible to produce an optically active 2-amino-1-phenylethanol derivative from a 2-amino-1-phenylethanol compound having one asymmetric carbon atom within its molecule through the use of a specific microorganism. The present state of art is, however, that there has been no efficient process for producing xcex2-amino alcohol having two asymmetric carbon atoms.
This invention has been made in view of the above-indicated circumstances and it aims at producing a xcex2-amino alcohol having the desired optical activity from an enantiomeric mixture of an xcex1-aminoketone compound or its salt in a high yield as well as in a highly selective manner with a simple process while sufficiently preventing the generation of diastereomeric byproducts.
The present inventors repeated studies diligently to solve the above-stated problems; consequently, it was discovered that by utilizing specific microorganisms only one enantiomer of the enantiomeric mixture of an xcex1-aminoketone compound or its salt could be reduced to produce the only desired kind among the corresponding four kinds of xcex2-amino alcohols in a high yield as well as in a highly selective manner. This led to the completion of the present invention.
Specifically, the process for producing an optically active xcex2-amino alcohol according to this invention comprises allowing at least one microorganism selected from the group consisting of microorganisms belonging to the genus Morganella, the genus Microbacterium, the genus Sphingobacterium, the genus Nocardicides, the genus Mucor, the genus Absidia, the genus Aspergillus, the genus Penicillium, the genus Grifola, the genus Eurotium, the genus Ganoderma, the genus Hypocrea, the genus Helicostylum, the genus Verticillium, the genus Fusarium, the genus Tritirachium, the genus Mortierella, the genus Armillariella, the genus Cylindrocarpon, the genus Kiebsiella, the genus Aureobacterium, the genus Xanthomonas, the genus Pseudomonas, the genus Mycobacterium, the genus Sporobolomyces, the genus Sporidiobolus, the genus Amycolatopsis, the genus Coprinus, the genus Serratia, the genus Rhodococuss and the genus Rhodotorula to act on an enantiomeric mixture of an xcex1-aminoketone or a salt thereof having the general formula (1): 
wherein X may be the same or different and represents at least one member selected from the group consisting of a halogen atom, lower alkyl, hydroxyl optionally protected with a protecting group, nitro and sulfonyl; n represents an integer of from 0 to 3; R1 represents lower alkyl; R2 and R3 may be the same or different and represent at least one member selected from the group consisting of a hydrogen atom and lower alkyl; and xe2x80x9c*xe2x80x9d represents an asymmetric carbon, to produce an optically active xcex2-amino alcohol compound with the desired optical activity having the general formula (II): 
wherein X, n, R1, R2, R3 and xe2x80x9c*xe2x80x9d are as previously defined.
The microorganism according to this invention is preferably at least one microorganism selected from the group consisting of microorganisms belonging to Morganella morganii, Microbacterium arborescens, Sphingobacterium multivorum, Nocardioides simplex, Mucor ambiguus, Mucor javanicus, Mucor fragilis, Absidia lichtheimi, Aspergillus awamori, Aspergillus niger, Aspergillus oryzae, Aspergillus candidus, Aspergillus oryzae var. oryzae, Aspergillus foetidus var. acidus, Penicillium oxalicum, Grifola frondosa, Eurotium repens, Ganoderma lucidum, Hypocrea gelatinosa, Helicostylum nigricans, Verticillium fungicola var. fungicola, Fusarium roseum, Tritirachium oryzae, Mortierella isabellina, Armillariella mellea, Cylindrocarpon sclerotigenum, Klebsiella pneumoniae, Aureobacterium esteraromaticum, Xanthomonas sp., Pseudomonas putida, Mycobacterium smegmatis, Mycobacterium diernhoferi, Mycobacterium vaccae, Mycobacterium phlei, Mycobacterium fortuitum, Mycobacterium chlorophenolicum, Sporobolomyces salmonicolor, Sporobolomyces coralliformis, Sporidiobolus johnsonii, Amycolatopsis alba, Amycolatopsis azurea, Amycolatopsis coloradensis, Amycolatopsis orientalis lurida, Amycolatopsis orientalis orientalis, Coprinus rhizophorus, Serratia marcescens, Rhodococcus erythropolis, Rhodococcus rhodochrous and Rhodotorula aurantiaca. 
In this invention the microorganism is preferably at least one microorganism selected from the group consisting of microorganisms belonging to the genus Morganella, the genus Microbacterium, the genus Sphingobacterium, the genus Nocardioides, the genus Mucor, the genus Absidia, the genus Aspergillus, the genus Penicillium, the genus Grifola, the genus Eurotium, the genus Ganoderma, the genus Hypocrea, the genus Helicostylum, the genus Verticillium, the genus Fusarium, the genus Tritirachium, the genus Mortierella, the genus Armillariella, the genus Cylindrocarpon, the genus Klebsiella, the genus Aureobacterium, the genus Xanthomonas, the genus Pseudomonas, the genus Mycobacterium, the genus Sporobolomyces, the genus Sporidiobolus and the genus Rhodococuss. More specifically, it is preferably a microorganism selected from the group consisting of microorganisms belonging to Morganella morganii, Microbacterium arborescens, Sphingobacterium multivorum, Nocardioides simplex, Mucor ambiguus, Mucor javanicus, Mucor fragilis, Absidia lichtheimi, Aspergillus awamori, Aspergillus niger, Aspergillus oryzae, Aspergillus candidus, Aspergillus oryzae var. oryzae, Aspergillus foetidus var. acidus, Penicillium oxalicum, Grifola frondosa, Eurotium repens, Ganoderma lucidum, Hypocrea gelatinosa, Helicostylum nigricans, Verticillium fungicola var. fungicola, Fusarium roseum, Tritirachium, oryzae, Mortierella isabellina, Armillariella mellea, Cylindrocarpon sclerotigenum, Klebsiella pneumoniae, Aureobacterium esteraromaticum, Xanthomonas sp., Pseudomonas putida, Mycobacterium smegmatis, Mycobacterium diernhoferi, Mycobacterium vaccae, Mycobacterium phlei, Mycobacterium fortuitum, Mycobacterium chlorophenolicum, Sporobolomyces salmonicolor, Sporobolomyces coralliformis, Sporidiobolus johnsonii, Rhodococus erythropolis and Rhodococcus rhodochrous. By utilizing such microorganisms, (1S,2S)-amino alcohols tend to be obtained in simple processes as the optically active xcex2-amino alcohols represented by the general formula (II) in high yields as well as in a highly selective manner.
Further, the microorganism is preferably at least one microorganism selected from the group consisting of microorganisms belonging to the genus Amycolaptopsis, the genus Coprinus, the genus Serratia, the genus Rhodococuss and the genus Rhodotorula. More specifically, it is preferably a microorganism selected from the group consisting of microorganisms belonging to Amycolatopsis alba, Amycolatopsis azurea, Amycolatopsis coloradensis, Amycolatopsis orientalis lurida, Amycolatopsis orientalis orientalis, Coprinus rhizophorus, Serratia marcescens, Rhodococcus erythropolis, Rhodococcus rhodochrous and Rhodotorula aurantiaca. By utilizing such microorganisms, (1R,2R)-amino alcohols tend to be obtained in simple processes as the optically active xcex2-amino alcohols represented by the general formula (II) in high yields as well as in a highly selective manner.
Still further, in this invention the microorganism may be cultured in a medium to which there has been added an activity inducer having the general formula (III): 
wherein R4 represents lower alkyl; R5 and R6 may be the same or different and each represents a hydrogen atom, lower alkyl or acyl; and Y represents Cxe2x95x90O or CHxe2x80x94OH. The mediation of such an activity inducer renders the production of an optically active xcex2-amino alcohol more efficient.